Temsirolimus

pharmacological · immune-hematologic · IV

Temsirolimus. mTOR inhibitor — ester prodrug rapidly hydrolyzed to sirolimus in vivo. Approved for advanced renal cell carcinoma (IV weekly… IV half-life 17 h.

mTOR inhibitor — ester prodrug rapidly hydrolyzed to sirolimus in vivo. Approved for advanced renal cell carcinoma (IV weekly infusion). CYP3A4 substrate (the parent ester and the sirolimus metabolite). Largely displaced by oral everolimus + kinase inhibitors (sunitinib, pazopanib, cabozantinib) in modern RCC regimens. PK (Torisel label, 25 mg IV weekly): mean Cmax 585 ng/mL (CV 14%), AUC 1627 ng·h/mL (CV 26%), t½ 17.3 h (parent); 54.6 h sirolimus metabolite. Vss 172 L in whole blood. Hydrolyzed in vivo to sirolimus (active mTOR-inhibiting metabolite); both species contribute to clinical effect. CYP3A4 substrate.

PK: DIAGNOSED ENTIRELY FROM THE NUMBERS ALREADY WRITTEN IN ITS OWN SOURCE LABEL, WHICH TURN OUT TO BE MUTUALLY UNSATISFIABLE. That label string records a peak of 585 ng/mL, an exposure of 1627 ng·h/mL and a half-life of 17.3 hours. THOSE THREE GIVE AN EXPOSURE-TO-PEAK RATIO OF 2.78 HOURS AGAINST A FLOOR OF 24.96 — NEARLY NINE-FOLD BELOW — so no absorption rate, volume or bioavailability reproduces them; the drug has a distribution phase this model has no slot for. The stored volume is additionally labelled a Vss, which is the wrong volume for a model whose exposure must close, and the pair asserted a clearance of 6.9 L/h against the 15.4 the label own dose and exposure imply — 2.23-FOLD UNDER, while the peak simultaneously rendered four-fold LOW. Errors in opposite directions, so nothing fixes both. The everolimus verdict applies: PRESERVE EXPOSURE AND PAY ON THE PEAK, declared rather than discovered later. THAT MAKES TWO WHOLE-BLOOD-REFERENCED mTOR INHIBITORS whose concentrations the solver labels plasma — the same latent trap, now a pattern rather than an incident. AND THE ACTIVE METABOLITE IS ABSENT: this record models the parent, which its analyte field correctly declares, while sirolimus carries much of the activity and has a far longer half-life.

Pharmacokinetics

Sources: PMID:17020981